PCYC-1102 was intended for elderly patients. Although both 420 mg and 840 mg doses were planned, the 840 mg cohort was closed due to findings of comparable efficacy in other studies. NHLBI 12-H-0035 was intended for patients with p.TP53 aberrations. RESONATE-2 was intended for patients older than 65 years. CLL12 was intended for patients with asymptomatic Binet stage A CLL. Reported efficacy for RESONATE-2 is based on the 2018 update.

Chemotherapy

Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3 (note: there was ambiguity in Wierda et al. 2011 about whether both fludarabine and cyclophosphamide are given three days per cycle, or whether fludarabine is given once per cycle and only cyclophosphamide is given three days per cycle)

Variant #2

Chemotherapy

Optional alternate initial dosing for patients with WBC count greater than 100 x 109/L: 100 mg IV once on day 1, with remainder of the 375 mg/m2 dosage given on day 2

Initial infusion rate with first dose of rituximab: 50 mg/hr, then increased as tolerated by 50 mg/hr every 30 minutes to a maximum of 400 mg/hr. Infusion rate with subsequent doses of rituximab (if first dose tolerated): 100 mg/hr, then increased as tolerated by 100 mg/hr every 30 minutes to a maximum of 400 mg/hr.

Both 420 mg and 840 mg doses were investigated in PCYC-1102: "the similar response in the two dose groups provide support for the use of the 420-mg dose of ibrutinib for relapsed CLL." The others used the 420 mg dose. RESONATE-17 was intended for patients with 17p deletion.

Note: this regimen is sometimes described as 300 mg IV once on day 1, then 2000 mg IV once per week for 7 weeks, then 2000 mg IV once every 4 weeks for 16 weeks. We are not aware of any published results for DUO; we will add them when available. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3 (note: there was ambiguity in Wierda et al. 2011 about whether both fludarabine and cyclophosphamide are given three days per cycle, or whether fludarabine is given once per cycle and only cyclophosphamide is given three days per cycle)

For patients with WBC count greater than 50 x 109/L, bulky disease, or history of hyperuricemia: Allopurinol (Zyloprim) 300 mg PO once prior to first dose of Alemtuzumab (Campath), and used later if clinically indicated

Ibrutinib & Rituximab

Regimen

This study was open to patients with high-risk CLL (del17p or TP53 mutation, PFS less than 36 months from initial therapy, or relapsed CLL with del11q). Only 4 patients in the published study were untreated.

Binet staging (1981)

Group A: no anemia, no thrombocytopenia, less than three involved areas

Group B: no anemia, no thrombocytopenia, three or more involved areas (counting as one each of the following: axillary, cervical, inguinal, lymph nodes, whether unilateral or bilateral, spleen and liver)

Group C: anemia (hemoglobin less than 10 g/dL) and/or thrombocytopenia (platelets less than 100 x 109/L)

CLL-IPI (2016)

International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016 Jun;17(6):779-90. Epub 2016 May 13. link to original articlePubMed